Over 5 million Americans suffer from heart failure with over a half a million newly diagnosed cases each year. The annual cost of treatment is approaching 40 billion dollars with over 20 billion dollars in hospital expenses alone. The incidence of heart failure increases with age and is markedly higher amongst minority populations. Therefore, heart failure presents a major health problem in the United States as well as worldwide. Exercise intolerance is a classic symptom of heart failure. Even moderate exercise may leave the patient exhausted and out of breath. In this setting often extreme activation of the sympathetic nervous system occurs causing profound peripheral vasoconstriction. Even the coronary vasculature may be vasoconstricted causing local ischemia and increased incidence of ventricular arrhythmias and sudden cardiac death. The mechanisms mediating this exaggerated activation of the sympathetic nervous system during exercise in subjects with heart failure are poorly understood. Previous studies have implicated abnormal activation of the muscle metaboreflex and arterial baroreflex in mediating these responses. This competing renewal proposal is focused on expanding our investigations of altered neural control of cardiovascular function during exercise in heart failure. We will utilize our innovative and highly complex conscious, chronically instrumented canine model. Our long term goal is to further elucidate the mechanisms responsible for the heightened activation of the sympathetic nervous system during exercise in heart failure and the functional consequences of these responses in the integrative control of cardiovascular function. This proposal is focused on the altered neuronal control of coronary blood flow and the impact on ventricular function during exercise in heart failure as well as the role of vasoconstriction in active skeletal muscle in mediating the exaggerated sympathetic activation in this setting. A major strength of the proposal is our unique capability of simultaneous measurement of a number of critical central and peripheral hemodynamic parameters in real time at rest and during exercise in the same animals before and after induction of heart failure. These longitudinally designed experiments we feel will provide compelling new information on the altered mechanisms of cardiovascular control during exercise in heart failure. PUBLIC HEALTH RELEVANCE: Heart failure is one of the leading causes of death in the U.S. affecting over 5 million Americans with over 550,000 new cases diagnosed each year. A hallmark feature of heart failure is decreased exercise tolerance. Even in normal subjects, dynamic exercise presents one of the greatest challenges to cardiovascular control and this challenge is markedly exacerbated in heart failure resulting in often profound increases in sympathetic nerve activity which can elicit vasoconstriction of the coronary circulation as well as the active skeletal muscle. The focus of this proposal is to determine the roles of the muscle metaboreflex and arterial baroreflex in this altered control of integrative cardiovascular function during exercise in heart failure and the functional consequences of the heighted sympathetic tone on ventricular function and skeletal muscle blood flow.